Identification of activated receptor tyrosine kinases associated with liver metastasis of colorectal cancer
대장암의 간 전이시 활성화되는 수용체 티로신 키나제의 선별
Dept. of Medical Science/박사
Liver metastasis is one of the main causes of cancer-related death among patients with colorectal cancer (CRC). However, accurate prediction and diagnosis of liver metastasis of CRC are difficult at the inception of diagnosis. Activated receptor tyrosine kinases (RTKs) are the important mediators of the signaling pathway that transfer to intracellular mechanism, and regulate cell survival, proliferation, differentiation and apoptosis. To determine if any of these RTKs are involved in liver metastasis from CRC, we performed phospho-RTK array with matched 20 colon normal mucosa, primary tumor, metastatic liver tumor, and liver normal tissue proteins using human phospho-RTK array. The various RTKs were differentially activated among the tissue types. The 20 RTKs were highly activated in primary tumor tissues compared with colon normal mucosa. These receptors belong to the FGF, NGF, Eph, ROR, EGF, Tie, VEGF and PDGF receptor gene families which are related to cell survival, proliferation differentiation, vascular development, and angiogenesis. In this work, we found that 6 (VEGFR3, FGFR1, FGFR3, MSPR, Tie-2, and MuSK) out of the 20 activated RTKs evaluated were highly activated in metastatic liver tumor compared with primary colon tumor samples and FGFR1 activation was also increased in a high proportion of metastatic liver tumor (p < 0.05). In the in vitro experiment, we observed that inhibition of FGFR1 resulted in a loss of cell survival and proliferation, confirming a functional role for the activated FGFR1 related signaling pathway and decreased cell migration and invasion capacity. Moreover, we demonstrated that inhibition of selected RTKs significantly reduced liver metastasis of colon cancer cells as compared to the control group through in vivo orthotopic tumor models. These data showed that highly activation of RTKs and, in particular, FGFR1 activation is
important in tumor progression and metastasis through PI3K/AKT and MAPK signaling pathway. Our study may provide that selected RTKs activation may thus be a novel predictive marker of liver metastasis of CRC. In conclusion, it may work as potential target RTK in liver metastasis of CRC and helpful to understand the molecular mechanisms underlying tumor progression and metastasis.